Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Multiple Myeloma

Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Table 2: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups

System Organ Class/ Preferred Term

REVLIMID/Dex*(n=353)n (%)

Placebo/Dex *(n=350)n (%)

Blood and lymphatic system disorders

Neutropenia %

149 (42.2)

22 (6.3)

Anemia @

111 (31.4)

83 (23.7)

Thrombocytopenia @

76 (21.5)

37 (10.6)

Leukopenia

28 (7.9)

4 (1.1)

Lymphopenia

19 (5.4)

5 (1.4)

General disorders and administration site conditions

Fatigue

155 (43.9)

146 (41.7)

Pyrexia

97 (27.5)

82 (23.4)

Peripheral edema

93 (26.3)

74 (21.1)

Chest Pain

29 (8.2)

20 (5.7)

Lethargy

24 (6.8)

8 (2.3)

Gastrointestinal disorders

Constipation

143 (40.5)

74 (21.1)

Diarrhea@

136 (38.5)

96 (27.4)

Nausea @

92 (26.1)

75 (21.4)

Vomiting @

43 (12.2)

33 (9.4)

Abdominal Pain @

35 (9.9)

22 (6.3)

Dry Mouth

25 (7.1)

13 (3.7)

Musculoskeletal and connective tissue disorders

Muscle cramp

118 (33.4)

74 (21.1)

Back pain

91 (25.8)

65 (18.6)

Bone Pain

48 (13.6)

39 (11.1)

Pain in Limb

42 (11.9)

32 (9.1)

Nervous system disorders

Dizziness

82 (23.2)

59 (16.9)

Tremor

75 (21.2)

26 (7.4)

Dysgeusia

54 (15.3)

34 (9.7)

Hypoaesthesia

36 (10.2)

25 (7.1)

Neuropathy a

23 (6.5)

13 (3.7)

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea

83 (23.5)

60 (17.1)

Nasopharyngitis

62 (17.6)

31 (8.9)

Pharyngitis

48 (13.6)

33 (9.4)

Bronchitis

40 (11.3)

30 (8.6)

Infectionsb and infestations

Upper respiratory tract infection

87 (24.6)

55 (15.7)

Pneumonia @

48 (13.6)

29 (8.3)

Urinary Tract Infection

30 (8.5)

19 (5.4)

Sinusitis

26 (7.4)

16 (4.6)

Skin and subcutaneous system disorders

Rash c

75 (21.2)

33 (9.4)

Sweating Increased

35 (9.9)

25 (7.1)

Dry Skin

33 (9.3)

14 (4.0)

Pruritus

27 (7.6)

18 (5.1)

Metabolism and nutrition disorders

Anorexia

55 (15.6)

34 (9.7)

Hypokalemia

48 (13.6)

21 (6.0)

Hypocalcemia

31 (8.8)

10 (2.9)

Appetite Decreased

24 (6.8)

14 (4.0)

Dehydration

23 (6.5)

15 (4.3)

Hypomagnesaemia

24 (6.8)

10 (2.9)

Investigations

Weight Decreased

69 (19.5)

52 (14.9)

Eye disorders

Blurred vision

61 (17.3)

40 (11.4)

Vascular disorders

Deep vein thrombosis %

33 (9.3)

15 (4.3)

Hypertension

28 (7.9)

20 (5.7)

Hypotension

25 (7.1)

15 (4.3)

Table 3: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups

System Organ Class/ Preferred Term

REVLIMID/Dex#(n=353)n (%)

Placebo/Dex#(n=350)n (%)

Blood and lymphatic system disorders

Neutropenia %

118 (33.4)

12 (3.4)

Thrombocytopenia @

43 (12.2)

22 (6.3)

Anemia @

35 (9.9)

20 (5.7)

Leukopenia

14 (4.0)

1 (0.3)

Lymphopenia

10 (2.8)

4 (1.1)

Febrile Neutropenia %

8 (2.3)

0 (0.0)

General disorders and administration site conditions

Fatigue

23 (6.5)

17 (4.9)

Vascular disorders

Deep vein thrombosis %

29 (8.2)

12 (3.4)

Infectionsb and infestations

Pneumonia @

30 (8.5)

19 (5.4)

Urinary Tract Infection

5 (1.4)

1 (0.3)

Metabolism and nutrition disorders

Hypokalemia

17 (4.8)

5 (1.4)

Hypocalcemia

13 (3.7)

6 (1.7)

Hypophosphatemia

9 (2.5)

0 (0.0)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism@

14 (4.0)

3 (0.9)

Respiratory Distress @

4 (1.1)

0 (0.0)

Musculoskeletal and connective tissue disorders

Muscle weakness

20 (5.7)

10 (2.9)

Gastrointestinal disorders

Diarrhea @

11 (3.1)

4 (1.1)

Constipation

7 (2.0)

1 (0.3)

Nausea @

6 (1.7)

2 (0.6)

Cardiac disorders

Atrial fibrillation @

13 (3.7)

4 (1.1)

Tachycardia

6 (1.7)

1 (0.3)

Cardiac Failure Congestive @

5 (1.4)

1 (0.3)

Nervous System disorders

Syncope

10 (2.8)

3 (0.9)

Dizziness

7 (2.0)

3 (0.9)

Eye Disorders

Cataract

6 (1.7)

1 (0.3)

Cataract Unilateral

5 (1.4)

0 (0.0)

Psychiatric Disorder

Depression

10 (2.8)

6 (1.7)

Table 4: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups

For all tables above:

n – Number of Patients

* - All Treatment Emergent AEs with ≥5% of Patients in REVLIMID/ Dex and at Least 2% Difference in Proportion between the Two Arms - (Safety population)

# - All Treatment Emergent Grades 3 and 4 AEs with ≥1% Patients in REVLIMID/ Dex and at Least 1% Difference in Proportion between the Two Arms - (Safety population)

& - All Treatment Emergent Serious AEs with ≥1% Patients in REVLIMID/ Dex and at Least 1% Difference in Proportion between the Two Arms - (Safety population)

@ - ADRs with Death as an outcome

% - ADRs which were considered to be life threatening (if the outcome of the event was death, it is included with death cases)

a - All PTs under the MedDRA SMQ of Neuropathy of a peripheral sensory nature will be considered listed

b - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed

c - All PTs under HLT of Rash will be considered listed

Dex=dexamethasone

Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse events between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively. Discontinuations due to DVT adverse reactions were reported at comparable rates between groups.

Pulmonary embolism (PE) was reported as a serious adverse drug reaction including Grade 3/4 (3.7%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% in the placebo/dexamethasone group. Discontinuations due to PE adverse reactions were reported at comparable rates between groups.

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group.

Other Adverse Reactions

In these clinical studies of REVLIMID in patients with multiple myeloma, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:

Clinical Trials Experience in Myelodysplastic Syndromes

A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 5 summarizes the adverse events that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 6 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

[a] System organ classes and preferred terms are coded using the MedDRA dictionary. System organ classes and preferred terms are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an AE is counted only once in the AE category.

System organ class/Preferred term [a]

10 mg Overall(N=148)

Patients with at least one adverse event

148 (100.0)

Blood and Lymphatic System DisordersThrombocytopeniaNeutropeniaAnemiaLeukopeniaFebrile Neutropenia

Clinical Trials Experience in Mantle Cell Lymphoma

In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.

Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events.

Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)].

Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

REPORTS OF SUSPECTED REVLIMID SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Revlimid. The information is not vetted and should not be considered as verified clinical evidence.

Possible Revlimid side effects / adverse reactions in 96 year old female

Reported by a pharmacist from Italy on 2011-10-03

Patient: 96 year old female

Reactions: Death

Adverse event resulted in: death

Suspect drug(s):
Revlimid

Possible Revlimid side effects / adverse reactions in 71 year old male

Reported by a physician from Thailand on 2011-10-03

Patient: 71 year old male

Reactions: Lymphoma

Adverse event resulted in: death

Suspect drug(s):
Revlimid

Possible Revlimid side effects / adverse reactions in 59 year old male

Reported by a health professional (non-physician/pharmacist) from Germany on 2011-10-03